Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1.
We studied the oxidation capacity in liver biopsies of a series of extensive metabolizers (n = 10) and poor metabolizers (n = 2) as identified by in vivo phenotyping with dextromethorphan. Codeine and dextromethorphan were used as probe drugs in vitro. The data were compared with the contents of cytochrome P-450IID1 as quantitated by Western immunoblotting by use of a specific monoclonal antibody (MAb 114/2). The O-demethylation of codeine was highly correlated with the O-demethylation of dextromethorphan (r = 0.90). The N-demethylation of codeine was catalyzed at a considerably higher rate than the O-demethylation. The N-demethylation to O-demethylation ratio of codeine was 46 in the poor metabolizer and, on average, 6.2 (range, 2.6 to 11) in the extensive metabolizers, respectively. The band intensity in Western blots correlated with the rate of O-demethylation of codeine (r = 0.95) and of dextromethorphan (r = 0.88) in the extensive metabolizers. The comeasurement of the O-demethylation and N-demethylation of codeine may provide a tool with which to phenotype individuals in vitro with respect to the polymorphism of the cytochrome P-450IID1.
Mortimer
O
O
Division of Clinical Pharmacology, Akademiska Hospital, University of Uppsala, Sweden.
Persson
K
K
Ladona
M G
MG
Spalding
D
D
Zanger
U M
UM
Meyer
U A
UA
Rane
A
A
D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D003061:Codeine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D006801:Humans; D007981:Levorphanol / Q000031:analogs & derivatives*; D008862:Microsomes, Liver / Q000378:metabolism*; D009020:Morphine / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic
D000911:Antibodies, Monoclonal; D007981:Levorphanol; C010414:norcodeine; D003915:Dextromethorphan; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; D010090:Oxidoreductases, O-Demethylating; D010089:Oxidoreductases, N-Demethylating; D003061:Codeine